title: FGFR1 mutations cause Hartsfield syndrome, the unique association of holoprosencephaly and ectrodactyly.
abstract: BACKGROUND
  Harstfield syndrome is the rare and unique association of holoprosencephaly (HPE) and ectrodactyly, with or without cleft lip and palate, and variable additional features. All the reported cases occurred sporadically. Although several causal genes of HPE and ectrodactyly have been identified, the genetic cause of Hartsfield syndrome remains unknown. We hypothesised that a single key developmental gene may underlie the co-occurrence of HPE and ectrodactyly.
  
  
  METHODS
  We used whole exome sequencing in four isolated cases including one case-parents trio, and direct Sanger sequencing of three additional cases, to investigate the causative variants in Hartsfield syndrome.
  
  
  RESULTS
  We identified a novel FGFR1 mutation in six out of seven patients. Affected residues are highly conserved and are located in the extracellular binding domain of the receptor (two homozygous mutations) or the intracellular tyrosine kinase domain (four heterozygous de novo variants). Strikingly, among the six novel mutations, three are located in close proximity to the ATP's phosphates or the coordinating magnesium, with one position required for kinase activity, and three are adjacent to known mutations involved in Kallmann syndrome plus other developmental anomalies.
  
  
  CONCLUSIONS
  Dominant or recessive FGFR1 mutations are responsible for Hartsfield syndrome, consistent with the known roles of FGFR1 in vertebrate ontogeny and conditional Fgfr1-deficient mice. Our study shows that, in humans, lack of accurate FGFR1 activation can disrupt both brain and hand/foot midline development, and that FGFR1 loss-of-function mutations are responsible for a wider spectrum of clinical anomalies than previously thought, ranging in severity from seemingly isolated hypogonadotropic hypogonadism, through Kallmann syndrome with or without additional features, to Hartsfield syndrome at its most severe end.
authors.affiliation: Laboratoire de Bioinformatique des Génomes et des Réseaux (BiGRe), Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Simonis
authors.forename: Isabelle
authors.initials: I
authors.lastname: Migeotte
authors.forename: Nelle
authors.initials: N
authors.lastname: Lambert
authors.forename: Camille
authors.initials: C
authors.lastname: Perazzolo
authors.forename: Deepthi C
authors.initials: DC
authors.lastname: de Silva
authors.forename: Boyan
authors.initials: B
authors.lastname: Dimitrov
authors.forename: Claudine
authors.initials: C
authors.lastname: Heinrichs
authors.forename: Sandra
authors.initials: S
authors.lastname: Janssens
authors.forename: Bronwyn
authors.initials: B
authors.lastname: Kerr
authors.forename: Geert
authors.initials: G
authors.lastname: Mortier
authors.forename: Guy
authors.initials: G
authors.lastname: Van Vliet
authors.forename: Philippe
authors.initials: P
authors.lastname: Lepage
authors.forename: Georges
authors.initials: G
authors.lastname: Casimir
authors.forename: Marc
authors.initials: M
authors.lastname: Abramowicz
authors.forename: Guillaume
authors.initials: G
authors.lastname: Smits
authors.forename: Catheline
authors.initials: C
authors.lastname: Vilain
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D002971:Cleft Lip / Q000201:enzymology / Q000235:genetics*; D002972:Cleft Palate / Q000201:enzymology / Q000235:genetics*; D059472:Exome; D005260:Female; D005385:Fingers / Q000002:abnormalities*; D023281:Genomics; D006228:Hand Deformities, Congenital / Q000201:enzymology / Q000235:genetics*; D016142:Holoprosencephaly / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics*; D008607:Intellectual Disability / Q000201:enzymology / Q000235:genetics*; D017880:Limb Deformities, Congenital / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000737:chemistry / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1
keywords: Clinical genetics; Developmental; Genetics